Abstract Concentrations of ultrafine particles (UFP) are elevated near major roadways and highways. Evidence is strong that living in these areas is associated with substantial respiratory, cardiovascular and other adverse health outcomes. We have contributed to recent evidence of associations between chronic exposure to UFP and cardiovascular disease risk. Indeed, in response to these findings, including ours, there is growing use of in-building air filtration to reduce traffic-related pollution levels in homes and schools near highways, including market-based responses and city ordinances. There is, however, as yet, no empirical evidence that these measures improve health. This proposal builds on preliminary studies in which we conducted randomized crossover trials of in-home air filtration on a smaller scale (N= 20 and 23) and a controlled short term setting (N=77). Our randomized 2-hour exposure study showed that reducing PM with filtration can reduce blood pressure. Accordingly, we propose a blinded randomized crossover efficacy trial (N=240 households consisting of 288 participants) of High Efficiency Particulate Air (HEPA) filtration in near-highway homes that lack mechanical air-handling systems. Households will be randomized to 30 days of either filtration or sham filtration followed by a 30 washout period with a subsequent 30-day period of the alternative assignment. Room air filters that are commercially available will be placed in the bedroom and living room of each home. We will measure UFP and PM2.5 concentrations in 20% of the homes during filtration and sham periods and assess personal exposure in a subset of participants. We will also assess chemical composition of particulate air pollution in 10 homes/year for exploratory purposes that could lead to future lines of research. Our primary health endpoints will be participants? hsCRP and peripheral blood pressure, measures we have used in multiple observational studies of UFP as well as in our pilot filtration intervention studies. Secondary biological measures that contribute to understanding biological pathways will be IL-6 (inflammation), D-dimer (coagulation), metabolome, central pressure and arterial stiffness. The primary intention to treat analysis will compare outcomes between HEPA filtration to sham filtration. We will have 80% power to detect a difference of 0.6 mg/L in change in hsCRP and a difference in reduction in systolic blood pressure of 3.5 mmHg compared to participants who receive no filtration. Having participants serve as their own controls in the within-subject comparisons of intervention effectiveness increases our statistical power and eliminates the possibility of baseline imbalances in demographic and clinical characteristics. A social science evaluation will inform final adjustments to our approach at the start and also assess participant acceptance and experience with the intervention at the end. Our primary innovation is that this will be the first near highway HEPA intervention trial that is large enough and careful enough to be policy-relevant.